Disabling the Notch Pathway in Skeletal Stem Cells Greatly Improves Bone Density
Skeletal stem cells in the bone marrow produce cells responsible for creating bone tissue. Researchers here show that disabling the well-known notch pathway in these cells leads to a considerable increase in bone mineral density with age. This is a desirable outcome, slowing the onset of osteoporosis, a widespread condition of old age. Better ways to encourage greater deposition of bone extracellular matrix are much needed, given the only modest efficacy of present drugs used in the treatment of osteoporosis.
Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging.
To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.